진행성 위장관기질종양 환자에서 생존 예후인자로서의 p53 단백 과발현의 의의
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Abstract Backgrounds p53, as a cross-talk regulator, plays a key role in both cell-cycle and apoptosis control and is expressed in a group of cancers. Recent studies demonstrated its potential value for prognostic assessment in various types of cancers. This study investigated the immnunohistochemical expression of p53 in advanced gastrointestinal stromal tumors (GISTs) treated with first-line imatinib with and without other tyrosine kinase inhibitors (TKIs) and correlated this with known pretreatment prognostic factors and clinical outcomes. Material and methods One hundred and eighty patients with advanced GISTs treated with first-line imatinib in Asan Medical Center between 2001 and 2011 were explored. Pre-treatment paraffin-embedded tumor sections were stained with p53 antibody. Tumors with nuclear staining in >10% of tumor cells were scored as positive for p53 overexpression. The driver mutations of KIT and PDGFRA were examined by polymerase chain reaction and direct sequencing of tumor DNA. The correlations of p53 expression with major driver mutations, pretreatment clinicopathologic parameters, and clinical outcomes were analyzed. Results Overexpression of p53 was observed in 67 patients (37%) and was not associated with the primary GISTs site and the KIT or PDGFRA mutation status. There was no difference in the response and disease control rate with standard dose of imatinb (400 mg once daily) based on p53 overexpression status. In univariate analysis, p53 overexpression was marginally associated with worse overall survival (OS) [median 63.9 months (95% CI: 47.9-80.0) with p53 overexpression vs. median 92.3 months (95% CI: 76.6-107.9) with no p53 overexpression (p=0.060)]. Multivariate analysis, including previously identified pretreatment prognostic parameters, revealed that only KIT exon 11 mutation was an independent good prognostic factor for progression-free survival (PFS) [KIT exon 11 vs. exon 9: Hazard ration (HR); 0.440, 95% confidence interval (CI); 0.205-0.945, p=0.035]. p53 overexpression was of borderline significance (p53 overexpression vs. no p53 overexpression: HR;1.767, 95% CI; 0.955-3.270, p=0.070) in PFS. In multivariate analysis for OS, p53 overexpression was an independent pretreatment risk factor for worse OS (HR; 2.057, 95% CI; 1.047-4.038, p=0.036). However, more patients in the group that did not overexpress p53 received surgical resection of residual lesions following imatinib treatment and salvage TKIs treatments which were previously identified prognostic parameters for survival in GIST patients. Therefore, we could not exclude that these imbalances in post-treatment factors between the two groups may be attributable to differences in OS. Conclusions Our data suggests that p53 overexpression is a possible pretreatment prognostic indicator for OS in patients with advanced GISTs treated with first-line imatinib with and without other tyrosine kinase inhibitors.